A number of intravitreal sustained-release pharmaceuticals for small molecules have been investigated and marketed in the past years. Early implants delivering Ganciclovir (Vitrasert®) and Fluocinolone (Retisert®) showed long release periods but were non-biodegradable (Musch et al., 1997, New England Journal of Medicine 337:83; Jaffe et al., 2005, Ophthalmology 112:119). A number of adverse effects, material problems, and surgical problems were reported when removing the implants from the eye (Martin et al., 1997, Arch Ophthalmol-Chic 115:1389; Boyer et al., 1999, Am J Ophthalmol 127:349). Thus, interest shifted toward biodegradable implants.
The currently approved degradable implants for intravitreal application (Ozurdex®) are based on poly(lactic-co-glycolic acid) (PLGA) and release dexamethasone for around 6 months (Kuppermann et al., 2007, Arch Ophthalmol-Chic 2007, 125:309). For the preparation of the PLGA-implants, pressure, heat, solvents or a combination thereof is used to incorporate the active substance and to form the implant (Kimura et al., 2001, Ophthalmologica 215:143). This implies problems for the formulation of proteins due to their intrinsically lower stability as compared to many small molecules.
A possible solution to the formulation problem of proteins for sustained-release could be the use of viscous excipients instead of solid implants. These can simply be mixed with the lyophilized protein to form the final formulation. Poly(ortho esters) (POEs) of the third generation were the first viscous, polymeric liquids investigated toward sustained intravitreal release (Einmahl et al., 2000, J Biomed Mater Res 50:566). But due to the lack of storage stability (Merkli et al., 1996, Biomaterials 17:897), difficulties with sterilizability (Sintzel et al., 1998, International Journal of Pharmaceutics 175:165) and difficulties in synthesis and upscaling (Behar-Cohen et al., 2006, Advanced Drug Delivery Reviews 58:1182), they were soon followed by a new generation of POEs.
Fourth generation POEs (POEs IV) were easier to synthesize, and a control of the degradation rate was possible by adjusting the ratio of the used monomers (Gurny et al., 1998, Biomaterials 19:791). POEs IV were evaluated up to a clinical phase II study and showed good biocompatibility in the human eye (Behar-Cohen et al., 2006, Advanced Drug Delivery Reviews 58:1182). However, their period of degradation in vivo was much longer than the period of drug release, shifting interest toward new liquid polymer entities for sustained-release delivery in the eye. Consequently, there is a need for improved sustained-release delivery systems and formulations for administering proteins to treat ocular diseases.